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Updated: Jan 23, 2026
10:06
Imaging Mycobacterium tuberculosis in Mice with Reporter Enzyme Fluorescence
Published on: February 26, 2018
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Large-scale chemical-genetics yields new M. tuberculosis inhibitor classes
Eachan O Johnson1,2,3, Emily LaVerriere1,4, Emma Office1
1Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nature
|June 21, 2019
Summary
New drug discovery for tuberculosis (TB) is critical. A novel PROSPECT screening strategy identified over tenfold more potential antibiotic compounds by testing against bacterial strains lacking essential genes, revealing new drug targets.
Area of Science:
- Microbiology
- Drug Discovery
- Genetics
Background:
- Rising antibiotic resistance necessitates novel therapeutic strategies, particularly for Mycobacterium tuberculosis (Mtb).
- Conventional screening methods have proven insufficient for identifying new Mtb drugs.
Purpose of the Study:
- To develop and validate a new screening approach, PROSPECT, for identifying novel antibiotic compounds against Mtb.
- To overcome limitations of traditional screening by incorporating genetic information.
Main Methods:
- Engineered Mtb strains targeting 474 essential genes.
- Screened compound libraries against pools of these engineered strains.
- Analyzed over 8.5 million chemical-genetic interactions to identify active compounds and their targets.
Main Results:
- PROSPECT identified over tenfold more hits compared to screening wild-type Mtb.
- Chemical-genetic interactions provided direct insights into compound targets.
- Identified over 40 compounds targeting DNA gyrase, cell wall, tryptophan, folate biosynthesis, RNA polymerase, and EfpA.
- Optimized EfpA inhibitors demonstrated potent activity against wild-type Mtb.
Conclusions:
- The PROSPECT strategy is effective in discovering novel antibiotic inhibitors against Mtb.
- This approach can identify inhibitors for targets previously inaccessible to conventional drug discovery.
- PROSPECT accelerates the identification of drug candidates for high-priority pathogens like Mtb.
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